Enhanced sampling of pre-fusion dynamics of the SARS-CoV-2 glycosylated spike

We are in the midst of a global pandemic caused by the SARS-CoV-2 virus, which leads to the COVID-19 disease that has taken over 450,000 lives to date.1 There is an urgent need to develop vaccines or treatments against this virus. The main target for antibodies or antivirals is the spike protein which binds to human ACE2 receptors. This protein is heavily glycosylated, which aids in immune system evasion. Molecular dynamics simulations play an important role in understanding the conformational dynamics of the spike protein, however conventional methods are limited in sampling to the microsecond regime. This project will use the enhanced sampling weighted ensemble method to reach biologically relevant timescales of the spike protein. The rigorous statistics inherent to the weighted ensemble method will allow for kinetically accurate sampling of the transition from the closed to open state of the spike protein, thus enabling an understanding of this important mechanistic movement in the virus-host-cell recognition process. In addition, our simulations will provide a vast array of intermediate conformations which can be useful for designing treatments against COVID-19 as well as understanding how neutralizing antibodies may bind.